The present invention relates to pharmaceutical agents which are xcex1vxcex23 and/or xcex1vxcex25 integrin antagonists and as such are useful in pharmaceutical compositions and in methods for treating conditions mediated by xcex1vxcex23 and/or xcex1vxcex25 integrins.
Integrins are a group of cell surface glycoproteins which mediate cell adhesion and therefore are useful mediators of cell adhesion interactions which occur during various biological processes. Integrins are heterodimers composed of noncovalently linked xcex1 and xcex2 polypeptide subunits. Currently eleven different xcex1 subunits have been identified and six different xcex2 subunits have been identified. The various xcex1 subunits can combine with various xcex2 subunits to form distinct integrins.
The integrin identified as xcex1vxcex23 (also known as the vitronectin receptor) has been identified as an integrin which plays a role in various conditions or disease states including tumor metastasis, solid tumor growth (neoplasia), osteoporosis (Ross, et al., J. Biol, Chem., 1987, 262, 7703), Paget""s disease, humoral hypercalcemia of malignancy (Carron et al., Cancer Res. 1998, 58, 1930), osteopenia (Lark et al., J Bone Miner Res. 2001, 16, 319), endometriosis (Healy et al., Hum. Reproductive Update, 1998, 4, 736), angiogenesis, including tumor angiogenesis (Cheresh, Cancer Metastasis Rev., 1991, 10, 3-10 and Brooks, et al., Cell, 1994, 79, 1157), retinopathy including macular degeneration (Friedlander et al., Proc. Natl. Acad. Sci USA 1996, 93, 9764), arthritis, including rheumatoid arthritis (Badger et al., Arthritis Rheum, 2001, 44, 128), periodontal disease, psoriasis and smooth muscle cell migration (e.g. restenosis and artherosclerosis, (Brown et al., Cardiovascular Res., 1994, 28, 1815). The compounds of the present invention are xcex1vxcex23 antagonists and can be used, alone or in combination with other therapeutic agents, in the treatment or modulation of various conditions or disease states described above. Additionally, it has been found that such agents would be useful as antivirals, antifungals and antimicrobials. Thus, compounds which selectively antagonize xcex1vxcex23 would be beneficial for treating such conditions.
The integrin xcex1vxcex25 plays a role in neovascularization. Antagonists of the xcex1vxcex25 integrin will inhibit neovascularization and will be useful for treating and preventing angiogenesis metastasis, tumor growth, macular degeneration and diabetic retionopathy. M. C. Friedlander, et al., Science, 270, 1500-1502 (1995) disclose that a monoclonal antibody for xcex1vxcex25 inhibits VEFG-induced angogenesis in the rabbit cornea and the chick chorioallantoic membrane model. Therefore, it would be useful to antagonize both the xcex1vxcex25 and the xcex1vxcex23 receptor. Such xe2x80x9cmixed xcex1vxcex25/xcex1vxcex23 antagonistsxe2x80x9d or xe2x80x9cdual xcex1vxcex23/xcex1vxcex25 antagonistsxe2x80x9d would be useful for treating or preventing angiogenesis, tumor metastasis, tumor growth, diabetic retinopathy, macular degeneration, atherosclerosis and osteoporosis.
It has been shown that the xcex1vxcex23 integrin and other xcex1v containing integrins bind to a number of Arg-Gly-Asp (RGD) containing matrix macromolecules. Compounds containing the RGD sequence mimic extracellular matrix ligands so as to bind to cell surface receptors. However, it is also known that RGD peptides in general are non-selective for RGD dependent integrins. For example, most RGD peptides which bind to xcex1vxcex23 also bind to xcex1vxcex25, xcex1vxcex21 and xcex1IIbxcex23. Antagonism of platelet xcex1IIbxcex23 (also known as the fibrinogen receptor) is known to block platelet aggregation in humans. In order to avoid bleeding side-effects when treating the conditions or disease states associated with the integrin xcex1vxcex23, it would be beneficial to develop compounds which are selective antagonists of xcex1vxcex23 as opposed to xcex1IIbxcex23.
Further, it has not been established in the art that sparing xcex1vxcex26 integrin would be a beneficial property to be incorporated in the design of antagonists of xcex1vxcex23. Rather, xcex1vxcex26 has been identified as a target for antagonists because it is higly expressed in many carcinoma cell lines, and has been shown to enchance the proliferative capacity of a colon carcinoma cell line both in vivo and in vitro (Agrez et al., 1994, J. Cell Biol. 127, 547). Additionally, xcex1vxcex26 is expressed during the later stages of wound healing and remains expressed until the wound is closed (See Christofidou-Solomidou, et al., 1997 American J. of Pathol., 151, 975), and therefore it is believed that xcex1vxcex26 plays a role in the remodeling of the vasculature during the later stages of angiogenesis. Accordingly, antagonists of xcex1vxcex26 are seen as useful in treating or preventing cancer by inhibiting tumor growth and metastasis (see, for example, U.S. Pat. No. 6,211,191).
Tumor cell invasion occurs by a three step process: 1) tumor cell attachment to extracellular matrix; 2) proteolytic dissolution of the matrix; and 3) movement of the cells through the dissolved barrier. This process can occur repeatedly and can result in metastases at sites distant from the original tumor.
Seftor et al. (Proc. Natl. Acad. Sci. USA, Vol. 89 (1992) 1557-1561) have shown that the xcex1vxcex23 integrin has a biological function in melanoma cell invasion. Montgomery et al., (Proc. Natl. Acad. Sci. USA, Vol. 91 (1994) 8856-60) have demonstrated that the integrin xcex1vxcex23 expressed on human melanoma cells promotes a survival signal, protecting the cells from apoptosis. Mediation of the tumor cell metastatic pathway by interference with the xcex1vxcex23 integrin cell adhesion receptor to impede tumor metastasis would be beneficial.
Brooks et al. (Cell, Vol. 79 (1994) 1157-1164) have demonstrated that antagonists of xcex1vxcex23 provide a therapeutic approach for the treatment of neoplasia (inhibition of solid tumor growth) since systemic administration of xcex1vxcex23 antagonists causes dramatic regression of various histologically distinct human tumors.
The adhesion receptor integrin xcex1vxcex23 was identified as a marker of angiogenic blood vessels in chick and man and therefore such receptor plays a critical role in angiogenesis or neovascularization. Angiogenesis is characterized by the invasion, migration and proliferation of smooth muscle and endothelial cells. Antagonists of xcex1vxcex23 inhibit this process by selectively promoting apoptosis of cells in neovasculature. The growth of new blood vessels, or angiogenesis, also contributes to pathological conditions such as diabetic retinopathy including macular degeneration (Adamis et al., Amer. J. Ophthal., Vol. 118, (1994) 445-450) and rheumatoid arthritis (Peacock et al., J. Exp. Med., Vol. 175, (1992), 1135-1138). Therefore, xcex1vxcex23 antagonists would be useful therapeutic agents for treating such conditions associated with neovascularization (Brooks et al., Science, Vol. 264, (1994), 569-571).
It has been reported that the cell surface receptor xcex1vxcex23 is the major integrin on osteoclasts responsible for attachment to bone. Osteoclasts cause bone resorption and when such bone resorbing activity exceeds bone forming activity it results in osteoporosis (loss of bone), which leads to an increased number of bone fractures, incapacitation and increased mortality. Antagonists of xcex1vxcex23 have been shown to be potent inhibitors of osteoclastic activity both in vitro [Sato et al., J. Cell. Biol., Vol. 111 (1990) 1713-1723] and in vivo [Fisher et al., Endocrinology, Vol. 132 (1993) 1411-1413]. Antagonism of xcex1vxcex23 leads to decreased bone resorption and therefore restores a normal balance of bone forming and resorbing activity. Thus it would be beneficial to provide antagonists of osteoclast xcex1vxcex23 which are effective inhibitors of bone resorption and therefore are useful in the treatment or prevention of osteoporosis.
The role of the xcex1vxcex23 integrin in smooth muscle cell migration also makes it a therapeutic target for prevention or inhibition of neointimal hyperplasia which is a leading cause of restenosis after vascular procedures (Choi et al., J. Vasc. Surg. Vol. 19(1) (1994) 125-34). Prevention or inhibition of neointimal hyperplasia by pharmaceutical agents to prevent or inhibit restenosis would be beneficial.
White (Current Biology, Vol. 3(9)(1993) 596-599) has reported that adenovirus uses xcex1vxcex23 for entering host cells. The integrin appears to be required for endocytosis of the virus particle and may be required for penetration of the viral genome into the host cell cytoplasm. Thus compounds which inhibit xcex1vxcex23 would find usefulness as antiviral agents.
The compounds of this invention are 1) xcex1vxcex23 integrin antagonists; or 2) xcex1vxcex25 integrin antagonists; or 3) mixed or dual xcex1vxcex23/xcex1vxcex25 antagonists. The present invention includes compounds which inhibit the respective integrins and also includes pharmaceutical compositions comprising such compounds. The present invention further provides for methods for treating or preventing conditions mediated by the xcex1vxcex23 and/or xcex1vxcex25 receptors in a mammal in need of such treatment comprising administering a therapeutically effective amount of the compounds of the present invention and pharmaceutical compositions of the present invention. Administration of such compounds and compositions of the present invention inhibits angiogenesis, tumor metastasis, tumor growth, osteoporosis, Paget""s disease, humoral hypercalcemia of malignancy, retinopathy, macular degeneration, arthritis, periodontal disease, smooth muscle cell migration, including restenosis and artherosclerosis, and viral diseases.
The compounds of the present invention further show greater selectivity for the xcex1vxcex23 and/or xcex1vxcex25 integrin than for the xcex1vxcex26 integrin. It has been found that th selective antagonism of the xcex1vxcex23 integrin is desirable in that the xcex1vxcex26 integrin may play a role in normal physiological processes of tissue repair and cellular turnover that routinely occur in the skin and pulmonary tissue, and the inhibition of this function can be deleterious. Therefore, compounds of the present invention which selectively inihibit the xcex1vxcex23 integrin as opposed to the xcex1vxcex26 integrin have reduced side-effects associated with inhibtion of the xcex1vxcex26 integrin.
The present invention relates to a class of compounds represented by the Formula I. 
or a pharmaceutically acceptable salts thereof wherein 
Y is selected from the group consisting of Nxe2x80x94R1, O, and S;
y and z are independently selected from an integer selected form 0, 1, 2 and 3;
A is N or C;
R1 is selected from the group consisting of H, alkyl, aryl, hydroxy, alkoxy, cyano, nitro, amino, alkenyl, alkynyl, amido, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl, arylthiocarbonyl, acyloxymethoxycarbonyl, alkyl optionally substituted with one or more substituent selected from lower alkyl, halogen, hydroxyl, haloalkyl, cyano, nitro, carboxyl, amino, alkoxy, aryl or aryl optionally substituted with one or more halogen, haloalkyl, lower alkyl, alkoxy, cyano, alkylsulfonyl, alkylthio, nitro, carboxyl, amino, hydroxyl, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocycles, or fused monocyclic heterocycles, aryl optionally substituted with one or more substituent selected from halogen, haloalkyl, hydroxy, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, cyano, nitro, alkylthio, alkylsulfonyl, sulfonic acid, sulfonamide, carboxyl derivatives, amino, aryl, fused aryl, monocyclic heterocycles and fused monocyclic heterocycle, monocyclic heterocycles, and monocyclic heterocycles optionally substituted with one or more substituent selected from halogen, haloalkyl, lower alkyl, alkoxy, amino, nitro, hydroxy, carboxyl derivatives, cyano, alkylthio, alkylsulfonyl, sulfonic acid, sulfonamide, aryl or fused aryl; or
R1 taken together with R8 forms a 4-12 membered dinitrogen containing heterocycle optionally substituted with one or more substituent selected from the group consisting of lower alkyl, hydroxy, keto, alkoxy, halo, phenyl, amino, carboxyl or carboxyl ester, and fused phenyl; or
R1 taken together with R8 forms a 5 membered heteroaromatic ring optionally substituted with one or more substituent selected from lower alkyl, phenyl and hydroxy; or
R1 taken together with R8 forms a 5 membered heteroaromatic ring fused with a phenyl group;
R8 (when not taken together with R1) and R9 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aralkyl, amino, alkylamino, hydroxy, alkoxy, arylamino, amido, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxy, aryloxycarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl, arylthiocarbonyl, acyloxymethoxycarbonyl, cycloalkyl, bicycloalkyl, aryl, acyl, benzoyl, alkyl optionally substituted with one or more substituent selected from lower alkyl, halogen, hydroxy, haloalkyl, cyano, nitro, carboxyl derivatives, amino, alkoxy, thio, alkylthio, sulfonyl, aryl, aralkyl, aryl optionally substituted with one or more substituent selected from halogen, haloalkyl, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, alkylthio, haloalkylthio, thio, hydroxy, cyano, nitro, carboxyl derivatives, aryloxy, amido, acylamino, amino, alkylamino, dialkylamino, trifluoroalkoxy, trifluoromethyl, sulfonyl, alkylsulfonyl, haloalkylsulfonyl, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocycles, fused monocyclic heterocycles, aryl optionally substituted with one or more substituent selected from halogen, haloalkyl, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, alkylthio, haloalkylthio, thio, hydroxy, cyano, nitro, carboxyl derivatives, aryloxy, amido, acylamino, amino, alkylamino, dialkylamino, trifluoroalkoxy, trifluoromethylsulfonyl, alkylsulfonyl, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocycles, or fused monocyclic heterocycles, monocyclic heterocycles, monocyclic heterocycles optionally substituted with one or more substituent selected from halogen, haloalkyl, lower alkyl, alkoxy, aryloxy, amino, nitro, hydroxy, carboxyl derivatives, cyano, alkylthio, alkylsulfonyl, aryl, fused aryl, monocyclic and bicyclic heterocyclicalkyls, xe2x80x94SO2R10 wherein R10 is selected from the group consisting of alkyl, aryl and monocyclic heterocycles, all optionally substituted with one or more substituent selected from the group consisting of halogen, haloalkyl, alkyl, alkoxy, cyano, nitro, amino, acylamino, trifluoroalkyl, amido, alkylaminosulfonyl, alkylsulfonyl, alkylsulfonylamino, alkylamino, dialkylamino, trifluoromethylthio, trifluoroalkoxy, trifluoromethylsulfonyl, aryl, aryloxy, thio, alkylthio, and monocyclic heterocycles; and 
wherein R10 is defined as above; or
NR8 and R9 taken together form a 4-12 membered mononitrogen containing monocyclic or bicyclic ring optionally substituted with one or more substituent selected from lower alkyl, carboxyl derivatives, aryl or hydroxy and wherein said ring optionally contains a heteroatom selected from the group consisting of O, N and S; or 
xe2x80x83wherein Yxe2x80x2 is selected from the group consisting of alkyl, cycloalkyl, bicycloalkyl, aryl, monocyclic heterocycles, alkyl optionally substituted with aryl which can also be optionally substituted with one or more substituent selected from halo, haloalkyl, alkyl, nitro, hydroxy, alkoxy, aryloxy, aryl, or fused aryl, aryl optionally substituted with one or more substituent selected from halo, haloalkyl, hydroxy, alkoxy, aryloxy, aryl, fused aryl, nitro, methylenedioxy, ethylenedioxy, or alkyl, alkynyl, alkenyl, xe2x80x94Sxe2x80x94R11 and xe2x80x94OR11 wherein R11 is selected from the group consisting of H, alkyl, aralkyl, aryl, alkenyl, and alkynyl, or R11 taken together with R8 forms a 4-12 membered mononitrogen and monosulfur or monooxygen containing heterocyclic ring optionally substituted with lower alkyl, hydroxy, keto, phenyl, carboxyl or carboxyl ester, and fused phenyl, or R11 taken together with R8 is thiazole, oxazole, benzoxazole, or benzothiazole;
R8 is defined as above; or
Y1 (when Y1 is carbon) taken together with R8 forms a 4-12 membered mononitrogen or dinitrogen containing ring optionally substituted with alkyl, aryl, keto or hydroxy; or 
xe2x80x83wherein R1 and R8 taken together form a 5-8 membered dinitrogen containing heterocycle optionally substituted with one or more substituent selected from the group consisting of lower alkyl, hydroxy, keto, phenyl, or carboxyl derivatives; and R9 is selected from the group consisting of alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl, arylthiocarbonyl, or acyloxymethoxycarbonyl; or 
xe2x80x83wherein R1 and R8 taken together form a 5-8 membered dinitrogen containing heterocycle optionally substituted with hydroxy, keto, phenyl, or alkyl; and R9 are both selected from the group consisting of alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl, arylthiocarbonyl and acyloxymethoxycarbonyl;
R2, R3 and R4 are independently selected from one or more substituent selected from thegroup consisting of H, alkyl, hydroxy, alkoxy, aryloxy, halogen, haloalkyl, haloalkoxy, nitro, amino, alkylamino, acylamino, dialkylamino, cyano, alkylthio, alkylsulfonyl, carboxyl derivatives, trihaloacetamide, acetamide, aryl, fused aryl, cycloalkyl, thio, monocyclic heterocycles, fused monocyclic heterocycles, and X, wherein X is defined as above;
R5, R6 and R7 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, carboxyl derivatives, haloalkyl, cycloalkyl, monocyclic heterocycles, monocyclic heterocycles optionally substituted with alkyl, halogen, haloalkyl, cyano, hydroxy, aryl, fused aryl, nitro, alkoxy, aryloxy, alkylsulfonyl, arylsulfonyl, sulfonamide, thio, alkylthio, carboxyl derivatives, amino, amido, alkyl optionally substituted with one or more of halo, haloalkyl, hydroxy, alkoxy, aryloxy, thio, alkylthio, alkynyl, alkenyl, alkyl, arylthio, alkylsulfoxide, alkylsulfonyl, arylsulfoxide, arylsulfonyl, cyano, nitro, amino, alkylamino, dialkylamino, alkylsulfonamide, arylsulfonamide, acylamide, carboxyl derivatives, sulfonamide, sulfonic acid, phosphonic acid derivatives, phosphinic acid derivatives, aryl, arylthio, arylsulfoxide, or arylsulfone all optionally substituted on the aryl ring with halo, alkyl, haloalkyl, cyano, nitro, hydroxy, carboxyl derivatives, alkoxy, aryloxy, amino, alkylamino, dialkylamino, amido, aryl, fused aryl, monocyclic heterocycles, and fused monocyclic heterocycles, monocyclic heterocyclicthio, monocyclic heterocyclicsulfoxide, and monocyclic heterocyclic sulfone, which can be optionally substituted with halo, haloalkyl, nitro, hydroxy, alkoxy, fused aryl, or alkyl, alkylcarbonyl, haloalkylcarbonyl, and arylcarbonyl, aryl optionally substituted in one or more positions with halo, haloalkyl, alkyl, alkoxy, aryloxy, methylenedioxy, ethylenedioxy, alkylthio, haloalkylthio, thio, hydroxy, cyano, nitro, acyloxy, carboxyl derivatives, carboxyalkoxy, amido, acylamino, amino, alkylamino, dialkylamino, trifluoroalkoxy, trifluoromethylsulfonyl, alkylsulfonyl, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocycles and fused monocyclic heterocycles.
The compounds according to Formula I can exist in various isomers, enantiomers, tautomers, racemates and polymorphs, and all such forms are meant to be included.
It is another object of the invention to provide pharmaceutical compositions comprising compounds of the Formula I. Such compounds and compositions are useful in selectively inhibiting or antagonizing the xcex1vxcex23 and/or xcex1vxcex25 integrins and therefore in another embodiment the present invention relates to a method of selectively inhibiting or antagonizing the xcex1vxcex23 and/or xcex1vxcex25 integrin. The invention further involves treating or inhibiting pathological conditions associated therewith such as osteoporosis, humoral hypercalcemia of malignancy, Paget""s disease, tumor metastasis, solid tumor growth (neoplasia), angiogenesis, including tumor angiogenesis, retinopathy including macular degeneration and diabetic retinopathy, arthritis, including rheumatoid arthritis, periodontal disease, psoriasis, smooth muscle cell migration and restenosis in a mammal in need of such treatment. Additionally, such pharmaceutical agents are useful as antiviral agents, and antimicrobials.
In its broadest sense, the invention relates to compounds represented by Formula I
The present invention relates to compound represented by Formula I 
or a pharmaceutically acceptable salts thereof wherein 
Y is selected from the group consisting of Nxe2x80x94R1, O, and S;
y and z are independently selected from an integer selected form 0, 1, 2 and 3;
A is N or C;
R1 is selected from the group consisting of H, alkyl, aryl, hydroxy, alkoxy, cyano, nitro, amino, alkenyl, alkynyl, amido, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl, arylthiocarbonyl, acyloxymethoxycarbonyl, alkyl optionally substituted with one or more substituent selected from lower alkyl, halogen, hydroxyl, haloalkyl, cyano, nitro, carboxyl, amino, alkoxy, aryl or aryl optionally substituted with one or more halogen, haloalkyl, lower alkyl, alkoxy, cyano, alkylsulfonyl, alkylthio, nitro, carboxyl, amino, hydroxyl, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocycles, or fused monocyclic heterocycles, aryl optionally substituted with one or more substituent selected from halogen, haloalkyl, hydroxy, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, cyano, nitro, alkylthio, alkylsulfonyl, sulfonic acid, sulfonamide, carboxyl derivatives, amino, aryl, fused aryl, monocyclic heterocycles and fused monocyclic heterocycle, monocyclic heterocycles, and monocyclic heterocycles optionally substituted with one or more substituent selected from halogen, haloalkyl, lower alkyl, alkoxy, amino, nitro, hydroxy, carboxyl derivatives, cyano, alkylthio, alkylsulfonyl, sulfonic acid, sulfonamide, aryl or fused aryl; or
R1 taken together with R8 forms a 4-12 membered dinitrogen containing heterocycle optionally substituted with one or more substituent selected from the group consisting of lower alkyl, hydroxy, keto, alkoxy, halo, phenyl, amino, carboxyl or carboxyl ester, and fused phenyl; or
R1 taken together with R8 forms a 5 membered heteroaromatic ring optionally substituted with one or more substituent selected from lower alkyl, phenyl and hydroxy; or
R1 taken together with R8 forms a 5 membered heteroaromatic ring fused with a phenyl group;
R8 (when not taken together with R1) and R9 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aralkyl, amino, alkylamino, hydroxy, alkoxy, arylamino, amido, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxy, aryloxycarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl, arylthiocarbonyl, acyloxymethoxycarbonyl, cycloalkyl, bicycloalkyl, aryl, acyl, benzoyl, alkyl optionally substituted with one or more substituent selected from lower alkyl, halogen, hydroxy, haloalkyl, cyano, nitro, carboxyl derivatives, amino, alkoxy, thio, alkylthio, sulfonyl, aryl, aralkyl, aryl optionally substituted with one or more substituent selected from halogen, haloalkyl, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, alkylthio, haloalkylthio, thio, hydroxy, cyano, nitro, carboxyl derivatives, aryloxy, amido, acylamino, amino, alkylamino, dialkylamino, trifluoroalkoxy, trifluoromethyl, sulfonyl, alkylsulfonyl, haloalkylsulfonyl, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocycles, fused monocyclic heterocycles, aryl optionally substituted with one or more substituent selected from halogen, haloalkyl, lower alkyl, alkoxy, methylenedioxy, ethylenedioxy, alkylthio, haloalkylthio, thio, hydroxy, cyano, nitro, carboxyl derivatives, aryloxy, amido, acylamino, amino, alkylamino, dialkylamino, trifluoroalkoxy. trifluoromethylsulfonyl, alkylsulfonyl, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocycles, or fused monocyclic heterocycles, monocyclic heterocycles, monocyclic heterocycles optionally substituted with one or more substituent selected from halogen, haloalkyl, lower alkyl, alkoxy, aryloxy, amino, nitro, hydroxy, carboxyl derivatives, cyano, alkylthio, alkylsulfonyl, aryl, fused aryl, monocyclic and bicyclic heterocyclicalkyls, xe2x80x94SO2R10 wherein R10 is selected from the group consisting of alkyl, aryl and monocyclic heterocycles, all optionally substituted with one or more substituent selected from the group consisting of halogen, haloalkyl, alkyl, alkoxy, cyano, nitro, amino, acylamino, trifluoroalkyl, amido, alkylaminosulfonyl, alkylsulfonyl, alkylsulfonylamino, alkylamino, dialkylamino, trifluoromethylthio, trifluoroalkoxy, trifluoromethylsulfonyl, aryl, aryloxy, thio, alkylthio, and monocyclic heterocycles; and 
xe2x80x83wherein R10 is defined as above; or
NR8 and R9 taken together form a 4-12 membered mononitrogen containing monocyclic or bicyclic ring optionally substituted with one or more substituent selected from lower alkyl, carboxyl derivatives, aryl or hydroxy and wherein said ring optionally contains a heteroatom selected from the group consisting of O, N and S; or 
xe2x80x83wherein Yxe2x80x2 is selected from the group consisting of alkyl, cycloalkyl, bicycloalkyl, aryl, monocyclic heterocycles, alkyl optionally substituted with aryl which can also be optionally substituted with one or more substituent selected from halo, haloalkyl, alkyl, nitro, hydroxy, alkoxy, aryloxy, aryl, or fused aryl, aryl optionally substituted with one or more substituent selected from halo, haloalkyl, hydroxy, alkoxy, aryloxy, aryl, fused aryl, nitro, methylenedioxy, ethylenedioxy, or alkyl, alkynyl, alkenyl, xe2x80x94Sxe2x80x94R11 and xe2x80x94OR11 wherein R11 is selected from the group consisting of H, alkyl, aralkyl, aryl, alkenyl, and alkynyl, or R11 taken together with R8 forms a 4-12 membered mononitrogen and monosulfur or monooxygen containing heterocyclic ring optionally substituted with lower alkyl, hydroxy, keto, phenyl, carboxyl or carboxyl ester, and fused phenyl, or R11 taken together with R8 is thiazole, oxazole, benzoxazole, or benzothiazole;
R8 is defined as above; or
Y1 (when Y1 is carbon) taken together with R8 forms a 4-12 membered mononitrogen or dinitrogen containing ring optionally substituted with alkyl, aryl, keto or hydroxy; or 
xe2x80x83wherein R1 and R8 taken together form a 5-8 membered dinitrogen containing heterocycle optionally substituted with one or more substituent selected from the group consisting of lower alkyl, hydroxy, keto, phenyl, or carboxyl derivatives; and R9 is selected from the group consisting of alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl, arylthiocarbonyl, or acyloxymethoxycarbonyl; or 
xe2x80x83wherein R1 and R8 taken together form a 5-8 membered dinitrogen containing heterocycle optionally substituted with hydroxy, keto, phenyl, or alkyl; and R9 are both selected from the group consisting of alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl, arylthiocarbonyl and acyloxymethoxycarbonyl;
R2, R3 and R4 are independently selected from one or more substituent selected from thegroup consisting of H, alkyl, hydroxy, alkoxy, aryloxy, halogen, haloalkyl, haloalkoxy, nitro, amino, alkylamino, acylamino, dialkylamino, cyano, alkylthio, alkylsulfonyl, carboxyl derivatives, trihaloacetamide, acetamide, aryl, fused aryl, cycloalkyl, thio, monocyclic heterocycles, fused monocyclic heterocycles, and X, wherein X is defined as above;
R5, R6 and R7 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, carboxyl derivatives, haloalkyl, cycloalkyl, monocyclic heterocycles, monocyclic heterocycles optionally substituted with alkyl, halogen, haloalkyl, cyano, hydroxy, aryl, fused aryl, nitro, alkoxy, aryloxy, alkylsulfonyl, arylsulfonyl, sulfonamide, thio, alkylthio, carboxyl derivatives, amino, amido, alkyl optionally substituted with one or more of halo, haloalkyl, hydroxy, alkoxy, aryloxy, thio, alkylthio, alkynyl, alkenyl, alkyl, arylthio, alkylsulfoxide, alkylsulfonyl, arylsulfoxide, arylsulfonyl, cyano, nitro, amino, alkylamino, dialkylamino, alkylsulfonamide, arylsulfonamide, acylamide, carboxyl derivatives, sulfonamide, sulfonic acid, phosphonic acid derivatives, phosphinic acid derivatives, aryl, arylthio, arylsulfoxide, or arylsulfone all optionally substituted on the aryl ring with halo, alkyl, haloalkyl, cyano, nitro, hydroxy, carboxyl derivatives, alkoxy, aryloxy, amino, alkylamino, dialkylamino, amido, aryl, fused aryl, monocyclic heterocycles, and fused monocyclic heterocycles, monocyclic heterocyclicthio, monocyclic heterocyclicsulfoxide, and monocyclic heterocyclic sulfone, which can be optionally substituted with halo, haloalkyl, nitro, hydroxy, alkoxy, fused aryl, or alkyl, alkylcarbonyl, haloalkylcarbonyl, and arylcarbonyl, aryl optionally substituted in one or more positions with halo, haloalkyl, alkyl, alkoxy, aryloxy, methylenedioxy, ethylenedioxy, alkylthio, haloalkylthio, thio, hydroxy, cyano, nitro, acyloxy, carboxyl derivatives, carboxyalkoxy, amido, acylamino, amino, alkylamino, dialkylamino, trifluoroalkoxy, trifluoromethylsulfonyl, alkylsulfonyl, sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic heterocycles and fused monocyclic heterocycles.
In another embodiment, the invention is represented by Formula II 
or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are selected from a group consisting of hydrogen, hydroxy alkyl haloalkyl and halogen.
The invention further relates to pharmaceutical compositions containing therapeutically effective amounts of the compounds of Formula I or II.
The invention also relates to a method of selectively inhibiting or antagonizing the xcex1vxcex23 integrin and/or the xcex1vxcex25 integrin and more specifically relates to a method of inhibiting bone resorption, periodontal disease, osteoporosis, humoral hypercalcemia of malignancy, Paget""s disease, tumor metastasis, solid tumor growth (neoplasia), angiogenesis, including tumor angiogenesis, retinopathy including macular degeneration and diabetic retinopathy, arthritis, including rheumatoid arthritis, smooth muscle cell migration and restenosis by administering a therapeutically effective amount of a compound of the Formula I to achieve such inhibition together with a pharmaceutically acceptable carrier. More specifically it has been found that it advantageous to administer compounds which are xcex1vxcex23 and/or xcex1vxcex25 antagonists which compounds selectively inhibit the xcex1vxcex23 and/or xcex1vxcex25 integrin as opposed to the xcex1vxcex26 integrin. It has now been found that such selectivity is beneficial in reducing unwanted side-effects.
To evaluate the selectivity of compounds between the integrins xcex1vxcex23 and xcex1vxcex26, cell-based assays are established using the 293 human embryonic kidney cell line as described herein. The compounds disclosed herein have shown significant selectivity between the integrins xcex1vxcex23 and xcex1vxcex26. The selective antagonism of the xcex1vxcex23 integrin is viewed as desirable in this class of compounds, as xcex1vxcex26 may also play a role in normal physiological processes of tissue repair and cellular turnover that routinely occur in the skin and pulmonary tissues.
As used herein, the terms xe2x80x9calkylxe2x80x9d or xe2x80x9clower alkylxe2x80x9d refer to a straight chain or branched chain hydrocarbon radicals having from about 1 to about 10 carbon atoms, and more preferably 1 to about 6 carbon atoms. Examples of such alkyl radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, neopentyl, hexyl, isohexyl, and the like.
As used herein the terms xe2x80x9calkenylxe2x80x9d or xe2x80x9clower alkenylxe2x80x9d refer to unsaturated acyclic hydrocarbon radicals containing at least one double bond and 2 to about 6 carbon atoms, which carbon-carbon double bond may have either cis or trans geometry within the alkenyl moiety, relative to groups substituted on the double bond carbons. Examples of such groups are ethenyl, propenyl, butenyl, isobutenyl, pentenyl, hexenyl and the like.
As used herein the terms xe2x80x9calkynylxe2x80x9d or xe2x80x9clower alkynylxe2x80x9d refer to acyclic hydrocarbon radicals containing one or more triple bonds and 2 to about 6 carbon atoms. Examples of such groups are ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like.
The term xe2x80x9ccycloalkylxe2x80x9d as used herein means saturated or partially unsaturated cyclic carbon radicals containing 3 to about 8 carbon atoms and more preferably 4 to about 6 carbon atoms. Examples of such cycloalkyl radicals include cyclopropyl, cyclopropenyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-cyclohexen-1-yl, and the like.
The term xe2x80x9carylxe2x80x9d as used herein denotes aromatic ring systems composed of one or more aromatic rings. Preferred aryl groups are those consisting of one, two or three aromatic rings. The term embraces aromatic radicals such as phenyl, pyridyl, naphthyl, thiophene, furan, biphenyl and the like.
As used herein, the term xe2x80x9ccyanoxe2x80x9d is represented by a radical 
The terms xe2x80x9chydroxyxe2x80x9d and xe2x80x9chydroxylxe2x80x9d as used herein are synonymous and are represented by a radical 
The term xe2x80x9clower alkylenexe2x80x9d or xe2x80x9calkylenexe2x80x9d as used herein refers to divalent linear or branched saturated hydrocarbon radicals of 1 to about 6 carbon atoms.
As used herein the term xe2x80x9calkoxyxe2x80x9d refers to straight or branched chain oxy containing radicals. Examples of alkoxy groups encompassed include methoxy, ethoxy, n-propoxy, n-butoxy, isopropoxy, isobutoxy, sec-butoxy, t-butoxy and the like.
As used herein the terms xe2x80x9carylalkylxe2x80x9d or xe2x80x9caralkylxe2x80x9d refer to a radical of the formula 
wherein R21 is aryl as defined above and R22 is an alkylene as defined above. Examples of aralkyl groups include benzyl, pyridylmethyl, naphthylpropyl, phenethyl and the like.
As used herein the term xe2x80x9cnitroxe2x80x9d is represented by a radical 
As used herein the term xe2x80x9chaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d refers to bromo, chloro, fluoro or iodo.
As used herein the term xe2x80x9chaloalkylxe2x80x9d refers to alkyl groups as defined above substituted with one or more of the same or different halo groups at one or more carbon atom. Examples of haloalkyl groups include trifluoromethyl, dichloroethyl, fluoropropyl and the like.
As used herein the term xe2x80x9ccarboxylxe2x80x9d or xe2x80x9ccarboxyxe2x80x9d refers to a radical of the formula xe2x80x94COOH.
As used herein the term xe2x80x9ccarboxyl esterxe2x80x9d refers to a radical of the formula xe2x80x94COOR23 wherein R23 is selected from the group consisting of H, alkyl, aralkyl or aryl as defined above.
As used herein the term xe2x80x9ccarboxyl derivativexe2x80x9d refers to a radical of the formula 
wherein Y6 and Y7 are independently selected from the group consisting of O, N or S and R23 is selected from the group consisting of H, alkyl, aralkyl and aryl as defined above.
As used herein the term xe2x80x9caminoxe2x80x9d is represented by a radical of the formula xe2x80x94NH2.
As used herein the term xe2x80x9calkylsulfonylxe2x80x9d or xe2x80x9calkylsulfonexe2x80x9d refers to a radical of the 
wherein R24 is alkyl as defined above.
As used herein the term xe2x80x9calkylthioxe2x80x9d refers to a radical of the formula xe2x80x94SR24 wherein R24 is alkyl as defined above.
As used herein the term xe2x80x9csulfonic acidxe2x80x9d refers to a radical of the 
wherein R25 is alkyl as defined above.
As used herein the term xe2x80x9csulfonamidexe2x80x9d or xe2x80x9csulfonamidoxe2x80x9d refers to a radical 
wherein R7 and R8 are as defined above.
As used herein the term xe2x80x9cfused arylxe2x80x9d refers to an aromatic ring such as the aryl groups defined above fused to one or more phenyl rings. Embraced by the term xe2x80x9cfused arylxe2x80x9d is the radical naphthyl and the like.
As used herein the terms xe2x80x9cmonocyclic heterocyclexe2x80x9d or xe2x80x9cmonocyclic heterocyclicxe2x80x9d refer to a monocyclic ring containing from 4 to about 12 atoms, and more preferably from 5 to about 10 atoms, wherein 1 to 3 of the atoms are heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur with the understanding that if two or more different heteroatoms are present at least one of the heteroatoms must be nitrogen. Representative of such monocyclic heterocycles are imidazole, furan, pyridine, oxazole, pyran, triazole, thiophene, pyrazole, thiazole, thiadiazole, and the like.
As used herein the term xe2x80x9cfused monocyclic heterocyclexe2x80x9d refers to a monocyclic heterocycle as defined above with a benzene fused thereto. Examples of such fused monocyclic heterocycles include benzofuran, benzopyran, benzodioxole, benzothiazole, benzothiophene, benzimidazole and the like.
As used herein the term xe2x80x9cmethylenedioxyxe2x80x9d refers to the radical 
and the term xe2x80x9cethylenedioxyxe2x80x9d refers to the radical 
As used herein the term xe2x80x9c4-12 membered dinitrogen containing heterocycle refers to a radical of the formula 
wherein m is 1 or 2 and R19 is H, alkyl, aryl, or aralkyl and more preferably refers to 4-9 membered ring and includes rings such as imidazoline.
As used herein the term xe2x80x9c5-membered optionally substituted heteroaromatic ringxe2x80x9d includes for example a radical of the formula 
and xe2x80x9c5-membered heteroaromatic ring fused with a phenylxe2x80x9d refers to such a xe2x80x9c5-membered heteroaromatic ringxe2x80x9d with a phenyl fused thereto. Representative of such 5-membered heteroaromatic rings fused with a phenyl is benzimidazole.
As used herein the term xe2x80x9cbicycloalkylxe2x80x9d refers to a bicyclic hydrocarbon radical containing 6 to about 12 carbon atoms which is saturated or partially unsaturated.
As used herein the term xe2x80x9cacylxe2x80x9d refers to a radical of the formula 
wherein R26 is alkyl, alkenyl, alkynyl, aryl or aralkyl and optionally substituted thereon as defined above. Encompassed by such radical are the groups acetyl, benzoyl and the like.
As used herein the term xe2x80x9cthioxe2x80x9d refers to a radical of the formula 
As used herein the term xe2x80x9csulfonylxe2x80x9d refers to a radical of the formula 
wherein R27 is alkyl, aryl or aralkyl as defined above.
As used herein the term xe2x80x9chaloalkylthioxe2x80x9d refers to a radical of the formula xe2x80x94Sxe2x80x94R28 wherein R28 is haloalkyl as defined above.
As used herein the term xe2x80x9caryloxyxe2x80x9d refers to a radical of the formula 
wherein R29 is aryl as defined above.
As used herein the term xe2x80x9cacylaminoxe2x80x9d refers to a radical of the formula 
wherein R30 is alkyl, aralkyl or aryl as defined above.
As used herein the term xe2x80x9camidoxe2x80x9d refers to a radical of the formula 
As used herein the term xe2x80x9calkylaminoxe2x80x9d refers to a radical of the formula xe2x80x94NHR32 wherein R32 is alkyl as defined above.
As used herein the term xe2x80x9cdialkylaminoxe2x80x9d refers to a radical of the formula xe2x80x94NR33R34 wherein R33 and R34 are the same or different alkyl groups as defined above.
As used herein the term xe2x80x9ctrifluoromethylxe2x80x9d refers to a radical of the formula 
As used herein the term xe2x80x9ctrifluoroalkoxyxe2x80x9d refers to a radical of the formula 
wherein R35 is a bond or an alkylene as defined above.
As used herein the term xe2x80x9calkylaminosulfonylxe2x80x9d or xe2x80x9caminosulfonylxe2x80x9d refers to a radical of the formula 
wherein R36 is alkyl as defined above.
As used herein the term xe2x80x9calkylsulfonylaminoxe2x80x9d or xe2x80x9calkylsulfonamidexe2x80x9d refers to a radical of the formula 
wherein R36 is alkyl as defined above.
As used herein the term xe2x80x9ctrifluoromethylthioxe2x80x9d refers to a radical of the formula 
As used herein the term xe2x80x9ctrifluoromethylsulfonylxe2x80x9d refers to a radical of the formula 
As used herein the term xe2x80x9c4-12 membered mono-nitrogen containing monocyclic or bicyclic ringxe2x80x9d refers to a saturated or partially unsaturated monocyclic or bicyclic ring of 4-12 atoms and more preferably a ring of 4-9 atoms wherein one atom is nitrogen. Such rings may optionally contain additional heteroatoms selected from nitrogen, oxygen or sulfur. Included within this group are morpholine, piperidine, piperazine, thiomorpholine, pyrrolidine, proline, azacycloheptene and the like.
As used herein the term xe2x80x9cbenzylxe2x80x9d refers to the radical 
As used herein the term xe2x80x9cphenethylxe2x80x9d refers to the radical 
As used herein the term xe2x80x9c4-12 membered mono-nitrogen containing monosulfur or monooxygen containing heterocyclic ringxe2x80x9d refers to a ring consisting of 4 to 12 atoms and more preferably 4 to 9 atoms wherein at least one atom is a nitrogen and at least one atom is oxygen or sulfur. Encompassed within this definition are rings such as thiazoline and the like.
As used herein the term xe2x80x9carylsulfonylxe2x80x9d or xe2x80x9carylsulfonexe2x80x9d refers to a radical of the formula 
wherein R37 is aryl as defined above.
As used herein the terms xe2x80x9calkylsulfoxidexe2x80x9d or xe2x80x9carylsulfoxidexe2x80x9d refer to radicals of the formula 
wherein R38 is, respectively, alkyl or aryl as defined above.
As used herein the term xe2x80x9carylthioxe2x80x9d refers to a radical of the formula 
wherein R42 is aryl as defined above.
As used herein the term xe2x80x9cmonocyclic heterocycle thioxe2x80x9d refers to a radical of the formula 
wherein R43 is a monocyclic heterocycle radical as defined above.
As used herein the terms xe2x80x9cmonocyclic heterocycle sulfoxidexe2x80x9d and xe2x80x9cmonocyclic heterocycle sulfonexe2x80x9d refer, respectively, to radicals 
wherein R43 is a monocyclic heterocycle radical as defined above.
As used herein the term xe2x80x9calkylcarbonylxe2x80x9d refers to a radical of the formula 
wherein R50 is alkyl as defined above.
As used herein the term xe2x80x9carylcarbonylxe2x80x9d refers to a radical of the formula 
wherein R51 is aryl as defined above.
As used herein the term xe2x80x9calkoxycarbonylxe2x80x9d refers to a radical of the formula 
wherein R52 is alkoxy as defined above.
As used herein the term xe2x80x9caryloxycarbonylxe2x80x9d refers to a radical of the formula 
wherein R51 is aryl as defined above.
As used herein the term xe2x80x9chaloalkylcarbonylxe2x80x9d refers to a radical of the formula 
R53 is haloalkyl as defined above.
As used herein the term xe2x80x9chaloalkoxycarbonylxe2x80x9d refers to a radical of the formula 
4 wherein R53 is haloalkyl as defined above.
As used herein the term xe2x80x9calkylthiocarbonylxe2x80x9d refers to a radical of the formula 
wherein R50 is alkyl as defined above.
As used herein the term xe2x80x9carylthiocarbonylxe2x80x9d refers to a radical of the formula 
wherein R51 is aryl as defined above.
As used herein the term xe2x80x9cacyloxymethoxycarbonylxe2x80x9d refers to a radical of the formula 
wherein R54 is acyl as defined above.
As used herein the term xe2x80x9carylaminoxe2x80x9d refers to a radical of the formula R51xe2x80x94NHxe2x80x94 wherein R51 is aryl as defined above.
As used herein the term xe2x80x9cacyloxyxe2x80x9d refers to a radical of the formula R55xe2x80x94Oxe2x80x94 wherein R55 is acyl as defined above.
As used herein the term xe2x80x9calkenylalkylxe2x80x9d refers to a radical of the formula R50xe2x80x94R57xe2x80x94 wherein R50 is an alkenyl as defined above and R57 is alkylene as defined above.
As used herein the term xe2x80x9calkenylenexe2x80x9d refers to a linear hydrocarbon radical of 1 to about 8 carbon atoms containing at least one double bond.
As used herein the term xe2x80x9calkoxyalkylxe2x80x9d refers to a radical of the formula R56xe2x80x94R57xe2x80x94 wherein R56 is alkoxy as defined above and R57 is alkylene as defined above.
As used herein the term xe2x80x9calkynylalkylxe2x80x9d refers to a radical of the formula R59xe2x80x94R60xe2x80x94 wherein R59 is alkynyl as defined as above and R60 is alkylene as defined as above.
As used herein the term xe2x80x9calkynylenexe2x80x9d refers to divalent alkynyl radicals of 1 to about 6 carbon atoms.
As used herein the term xe2x80x9callylxe2x80x9d refers of a radical of the formula xe2x80x94CH2CHxe2x95x90CH2.
As used herein the term xe2x80x9caminoalkylxe2x80x9d refers to a radical of the formula H2Nxe2x80x94R61 wherein R61 is alkylene as defined above.
As used herein the term xe2x80x9cbenzoylxe2x80x9d refers to the aryl radical C6H5xe2x80x94COxe2x80x94.
As used herein the term xe2x80x9ccarboxamidexe2x80x9d or xe2x80x9ccarboxamidoxe2x80x9d refer to a radical of the formula xe2x80x94COxe2x80x94NH2.
As used herein the term xe2x80x9ccarboxyalkylxe2x80x9d refers to a radical HOOCxe2x80x94R62xe2x80x94 wherein R62 is alkylene as defined as above.
As used herein the term xe2x80x9ccarboxylic acidxe2x80x9d refers to the radical xe2x80x94COOH.
As used herein the term xe2x80x9cetherxe2x80x9d refers to a radical of the formula R63xe2x80x94Oxe2x80x94 wherein R63 is selected from the group consisting of alkyl, aryl and heteroaryl.
As used herein the term xe2x80x9chaloalkylsulfonylxe2x80x9d refers to a radical of the formula 
wherein the R64 is haloalkyl as defined above.
As used herein the term xe2x80x9cheteroarylxe2x80x9d refers to an aryl radical contain at least one heteroatom.
As used herein the term xe2x80x9chydroxyalkylxe2x80x9d refers to a radical of the formula HOxe2x80x94R65xe2x80x94 wherein R65 is alkylene as defined above.
As used herein the term xe2x80x9cketoxe2x80x9d refers to a carbonyl group joined to 2 carbon atoms.
As used herein the term xe2x80x9clactonexe2x80x9d refers to an anhydro cyclic ester produced by intramolecular condensation of a hydroxy acid with the elimination of water.
As used herein the term xe2x80x9colefinxe2x80x9d refers to an unsaturated hydrocarbon radical of the type CnH2n.
As used herein the term xe2x80x9csulfonexe2x80x9d refers to a radical of the formula R66xe2x80x94SO2xe2x80x94.
As used herein the term xe2x80x9cthioalkylxe2x80x9d refers to a radical of the formula R77xe2x80x94SOxe2x80x94 wherein R77 is alkyl as defined above.
As used herein the term xe2x80x9cthioetherxe2x80x9d refers to a radical of the formula R78xe2x80x94Sxe2x80x94 wherein R78 is alkyl aryl or heteroaryl.
As used herein the term xe2x80x9ctrifluoroalkylxe2x80x9d refers to an alkyl radical as defined above substituted with three halo radicals as defined above.
The term xe2x80x9ccompositionxe2x80x9d as used herein means a product which results from the mixing or combining of more than one element or ingredient.
The term xe2x80x9cpharmaceutically acceptable carrierxe2x80x9d, as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a chemical agent.
The term xe2x80x9ctherapeutically effective amountxe2x80x9d shall mean that amount of drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system or animal that is being sought by a researcher or clinician.
The following is a list of abbreviations and the corresponding meanings as used interchangeably herein:
1H-NMR=proton nuclear magnetic resonance
AcOH=acetic acid
BOC=tert-butoxycarbonyl
BuLi=butyl lithium
Cat.=catalytic amount
CH2Cl2=dichloromethane
CH3CN=acetonitrile
CH3I=iodomethane
CHN analysis=carbon/hydrogen/nitrogen elemental analysis
CHNCl analysis=carbon/hydrogen/nitrogen/chlorine elemental analysis
CHNS analysis=carbon/hydrogen/nitrogen/sulfur elemental analysis
DEAD=diethylazodicarboxylate
DIAD=diisopropylazodicarboxylate
DI water=deionized water
DMA=N,N-dimethylacetamide
DMAC=N,N-dimethylacetamide
DMF=N,N-dimethylformamide
EDC=1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
Et=ethyl
Et2O=diethyl ether
Et3N=triethylamine
EtOAc=ethyl acetate
EtOH=ethanol
FAB MS=fast atom bombardment mass spectroscopy
g=gram(s)
HOBT=1-hydroxybenzotriazole hydrate
HPLC=high performance liquid chromatography
i-Pr=iso propyl
i-Prop=iso propyl
K2CO3=potassium carbonate
KMnO4=potassium permanganate
KOH=potassium hydroxide
KSCN=potassium thiocyanate
L=Liter
LiOH=lithium hydroxide
Me=methyl
MeOH=methanol
mg=milligram
MgSO4=magnesium sulfate
ml=milliliter
mL=milliliter
MS=mass spectroscopy
NaH=sodium hydride
NaHCO3=sodium bicarbonate
NaOH=sodium hydroxide
NaOMe=sodium methoxide
NH4+HCO2xe2x88x92=ammonium formate
NMR=nuclear magnetic resonance
Pd=palladium
Pd/C=palladium on carbon
Ph=phenyl
Pt=platinum
Pt/C=platinum on carbon
RPHPLC=reverse phase high performance liquid chromatography
RT=room temperature
t-BOC=tert-butoxycarbonyl
TFA=trifluoroacetic acid
THF=tetrahydrofuran
TLCxe2x80x94thin layer chromatography
TMS=trimethylsilyl
xcex94=heating the reaction mixture
The compounds as shown above can exist in various isomeric forms and all such isomeric forms are meant to be included. Tautomeric forms are also included as well as pharmaceutically acceptable salts of such isomers and tautomers.
In the structures and formulas herein, a bond drawn across a bond of a ring can be to any available atom on the ring.
The term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d refers to a salt prepared by contacting a compound of Formula I or II with an acid whose anion is generally considered suitable for human consumption. For use in medicine, the salts of the compounds of this invention are non-toxic xe2x80x9cpharmaceutically acceptable salts.xe2x80x9d Salts encompassed within the term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts include the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylgucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate/disphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g., sodium or potassium salts, alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts. All of the pharmacologically acceptable salts may be prepared by conventional means. (See Berge et al., J Pharm. Sci., 66(1), 1-19 (1977) for additional examples of pharmaceutically acceptable salts.)
The compounds of the present invention can have chiral centers and occur as racemates, racemic mixtures, diastereomeric mixtures, and as individual diastereomers or enantiomers, with all isomeric forms included in the present invention. Therefore, where a compound is chiral, the separate enantiomers or diastereomers, substantially free of the other, are included within the scope of the present invention; further included are all mixtures of the enantiomers or diastereomers. Also included within the scope of the invention are polymorphs, or hydrates or other modifiers of the compounds of invention.
The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds of this invention which are readily convertible in vivo into the required compound. For example, prodrugs of a carboxylic acid may include an ester, an amide, an ortho-ester, or heterocycles such as tetrazole. Thus, in the methods of treatment of the present invention, the term xe2x80x9cadministeringxe2x80x9d shall encompass the treatment of the various conditions described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in xe2x80x9cDesign of Prodrugs,xe2x80x9d ed. H. Bundgaard, Elsevier, 1985, which is incorporated by reference herein in its entirety. Metabolites of these compounds include active species produced upon introduction of compounds of this invention into the biological milieu.
For the selective inhibition or antagonism of xcex1vxcex23 and/or xcex1vxcex25 integrins, compounds of the present invention may be administered orally, parenterally, or by inhalation spray, or topically in unit dosage formulations containing conventional pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes, for example, subcutaneous, intravenous, intramuscular, intrasternal, transmuscular infusion techniques or intraperitonally.
The compounds of the present invention are administered by any suitable route in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. Therapeutically effective doses of the compounds required to prevent or arrest the progress of or to treat the medical condition are readily ascertained by one of ordinary skill in the art using preclinical and clinical approaches familiar to the medicinal arts.
Accordingly, the present invention provides a method of treating conditions mediated by selectively inhibiting or antagonizing the xcex1vxcex23 and/or xcex1vxcex25 cell surface receptor which method comprises administering a therapeutically effective amount of a compound selected from the class of compounds depicted in the above formulas, wherein one or more compound is administered in association with one or more non-toxic, pharmaceutically acceptable carriers and/or diluents and/or adjuvants (collectively referred to herein as xe2x80x9ccarrierxe2x80x9d materials) and if desired other active ingredients. The present invention also provides a method for selective inhibition of the xcex1vxcex23 and/or xcex1vxcex25 cell surface receptors with a reduced xcex1vxcex26 inhibition. Another aspect of the invention provides a method for inhibiting bone resorption, treating osteoporosis, inhibiting humoral hypercalcemia of malignancy, treating Paget""s disease, inhibiting tumor metastasis, inhibiting neoplasia (solid tumor growth), inhibiting angiogenesis including tumor angiogenesis, treating retinopathy including macular degeneration and diabetic retinopathy, inhibiting arthritis, psoriasis and periodontal disease, and inhibiting smooth muscle cell migration including restenosis.
In another embodiment, the present invention provides a method for selective antagonism of the xcex1vxcex23 and/or xcex1vxcex25 cell surface receptors over xcex1IIbxcex23, an in a further embodiment, also over the xcex1vxcex26 integrin receptor. Evidence of the toxicity of xcex26 integrin antagonism indicates that it may be beneficial to spare antagonism of xcex26 when designing xcex1vxcex23 antagonists, in addition to sparing xcex1IIbxcex23. Selectivite inhibition refers to a selectivity ratio of at least 10, more preferably 50, and even more preferably of at least 100. Selectivity ratio refers to the selectivity of the IC50 of xcex1vxcex26 or xcex1IIbxcex23 over the selectivity of the IC50 of xcex23.
Based upon standard laboratory experimental techniques and procedures well known and appreciated by those skilled in the art, as well as comparisons with compounds of known usefulness, the compounds of Formula I or II can be used in the treatment of patients suffering from the above pathological conditions. One skilled in the art will recognize that selection of the most appropriate compound of the invention is within the ability of one with ordinary skill in the art and will depend on a variety of factors including assessment of results obtained in standard assay and animal models.
Treatment of a patient afflicted with one of the pathological conditions comprises administering to such a patient an amount of compound of the Formula I which is therapeutically effective in controlling the condition or in prolonging the survivability of the patient beyond that expected in the absence of such treatment. As used herein, the term xe2x80x9cinhibitionxe2x80x9d of the condition refers to slowing, interrupting, arresting or stopping the condition and does not necessarily indicate a total elimination of the condition. It is believed that prolonging the survivability of a patient, beyond being a significant advantageous effect in and of itself, also indicates that the condition is beneficially controlled to some extent.
As stated previously, the compounds of the invention can be used in a variety of biological, prophylactic or therapeutic areas. It is contemplated that these compounds are useful in prevention or treatment of any disease state or condition wherein the xcex1vxcex23 and/or xcex1vxcex25 integrin plays a role.
The dosage regimen for the compounds and/or compositions containing the compounds is based on a variety of factors, including the type, age, weight, sex and medical condition of the patient; the severity of the condition; the route of administration; and the activity of the particular compound employed. Thus the dosage regimen may vary widely. Dosage levels of the order from about 0.01 mg to about 100 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions.
Oral dosages of the present invention, when used for the indicated effects, will range between about 0.01 mg per kg of body weight per day (mg/kg/day) to about 100 mg/kg/day, preferably 0.01 to 10 mg/kg/day, and most preferably 0.1 to 1.0 mg/kg/day. For oral administration, the compositions are preferably provided in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 200 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. A medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably, from about 1 mg to about 100 mg of active ingredient. Intravenous doses will range from about 0.1 to about 10 mg/kg/minute during a constant rate infusion. Compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, compounds of the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art. To be administered in the form of a transdermal delivery system, the dosage administration may be continuous rather than intermittant throughout the dosage regiment.
For administration to a mammal in need of such treatment, the compounds in a therapeutically effective amount are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. The compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulphuric acids, gelatin, acacia, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and tableted or encapsulated for convenient administration. Alternatively, the compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.
The pharmaceutical compositions useful in the present invention may be subjected to conventional pharmaceutical operations such as sterilization and/or may contain conventional pharmaceutical adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers, buffers, etc.
The following Schemes are intended to be merely illustrative of the present invention, and not limiting thereof in either scope or spirit. Those skilled in the art will readily understand that known variations of the conditions and processes described in the Schemes can be used to make the embodiments of the invention. 
The following Examples are intended to be illustrative and not intended to limit the scope of the invention.